Comparison of pulmonary vascular response to endogenous nitric oxide inhibition in sheep and pigs living at 2,300 m

To compare the role of nitric oxide in an adaptive process to chronic hypoxia, we examined the effects of endogenous nitric oxide synthase inhibition on pulmonary vascular tone in conscious sheep and pigs living at high altitude. Unanesthetized male sheep (n=6) and pigs (n=5), born and residing in the highlands of Qinghai Province, China (2,300–3,000 m a.s.l.) were studied at that altitude. Pulmonary artery pressure (P_pa), pulmonary artery wedge pressure (P_cwp), and cardiac output (CO) were measured. Pulmonary vascular resistance (PVR) was calculated as (P_pa—P_cwp)/CO. Using a climatic chamber, hemodynamic measurements during exposures to atmospheric pressures corresponding to altitudes of 0, 2,300, and 4,500 m a.s.l. were performed with and without NO inhibition, using N^w-nitro-l-argine (NLA; 20 mg kg^–1), a potent stereospecific competitive inhibitor of nitric oxide synthase. P_pa and PVR at baseline (2,300 m) and during hypoxic exposure (4,500 m) were significantly higher in pigs than in sheep. After NLA administration, P_pa increased and CO decreased in both animals, resulting in significantly increased PVR at baseline and during hypoxic exposure. However, there were no significant differences in the percent increase in basal or hypoxic PVR after NLA administration between sheep and pigs. We conclude that augmented endogenous NO production could contribute to the regulation of pulmonary vascular tone at high altitude in sheep and pigs. However, it is unlikely that NO is responsible for the different pulmonary vascular tones between sheep and pigs at basal condition at moderately high altitude.Communicated by G. Heldmaier     

Portal hemodynamic changes after hepatocyte transplantation in acute hepatic failure

Hepatocyte transplantation has been proposed as an alternative for rescuing patients with acute hepatic failure. However, portal hemodynamic changes and issues of safety after hepatocyte transplantation in acute hepatic failure have not been systemically evaluated because of the lack of a suitable experimentation system. In this study, we created a novel spring-guidewire introducer needle to simplify the technique for long-term portal cannulation in F-344 rats. The portal cannula was capable of being used for blood sampling, infusion of hepatocytes, and measurement of portal hemodynamic changes. One week after portal cannulation, rats were injected withD-galactosamine (1.35 g/kg, i.p.) to induce hepatic failure. Hepatocytes (2×10⁷) were infused intraportally 24–26 h after induction of liver injury. Portal pressures were recorded for up to 60 min after hepatocyte transplantation. Intraportal infusion of 2×10⁷ hepatocytes caused an instantaneous onset of portal hypertension. The magnitude of the rise in portal pressure was similar in both normal rats and rats with acute hepatic failure (33.0±7.1 vs. 37.7±0.5 mm Hg; p=0.23). However, the resolution rate of portal hypertension was remarkably delayed in rats with acute hepatic failure, and the portal pressure was significantly higher than that in normal rats 60 min after hepatocyte transplantation (25.0±2.8 vs. 14.5±2.4 mm Hg; p=0.007). In conclusion, we have established a simple new technique for long-term portal cannulation of rats. Our studies provide critical insights into the delayed resolution of portal hemodynamics after hepatocyte transplantation in subjects with acute hepatic failure.     

ATP敏感性钾通道开放剂埃他卡林对大鼠低氧性肺动脉高压的影响

目的 :探讨新型ATP敏感性钾通道开放剂 (KATPCO)埃他卡林 (iptkalim ,Ipt)对低氧性肺动脉高压 (HPH)大鼠肺血管重构的影响。方法 :将大鼠置于常压低氧舱内 (O2 1 0 %± 0 .5 % ) ,8h/d ,每周 6d ,4周后测定平均肺动脉压(mPAP)、RV/ (LV +S) ;用图象分析仪测量与呼吸性细支气管伴行的肺小动脉外径 (ED)、动脉中层壁厚 (MT)、动脉管壁中层面积 (MA)、动脉管腔面积 (VA)和血管总面积 (TAA)。结果 :慢性低氧组大鼠的mPAP和RV/ (LV +S)显著高于正常对照组 (P <0 .0 1 ) ;图象分析显示低氧组大鼠肺小动脉中层壁厚与动脉外径百分比 (MT % )、动脉壁中层面积与血管总面积百分比 (MA % )均显著高于对照组 (P <0 .0 1 ) ;慢性低氧组大鼠肺小动脉管腔面积 (VA)与血管总面积 (TAA)百分比显著低于正常组 (P <0 .0 1 )。Ipt 0 .75mg·kg- 1 ·d- 1 和 1 .50mg·kg- 1 ·d- 1 均可显著抑制低氧性肺血管壁重构 ,降低肺动脉压 ,减少右心室肥厚 ,1 .50mg·kg- 1 ·d- 1 则可逆转持续低氧所致的所有病理性变化。结论 :新型KATPCO埃他卡林是一个富有潜力的治疗HPH药物     

Sulphate influx in the erythrocytes of normotensive,diabetic and hypertensive patients

This study aimed to show that modifications in intracellular metabolism are implicated in the pathophysiology of diabetes mellitus and essential hypertension. In fact, total magnesium, calcium, sodium and potassium concentrations, measured in the erythrocytes of normotensive, diabetic and hypertensive patients, have given the following results: a lower intracellular potassium concentration in the erythrocytes of diabetic and hypertensive patients than the erythrocytes of normotensive patients and a more elevated sodium, magnesium, calcium concentrations in the erythrocytes of diabetic and hypertensive patients than the normotensive.Because of the importance of Mg2+ and Ca2+ in metabolic enzyme regulation and their interaction with both Hb and band 3 protein, we examined SO4(2-) kinetic influx in the erythrocytes of normotensive, hypertensive and diabetic patients. The kinetic plots showed different profiles over the three groups and the fluxes were found to be 0.024, 0.061 and 0.072 mmol x (l cells x min)(-1) in normotensive, hypertensive and diabetic patients, respectively. We also found that the Vmax and Km of sulphate influx, obtained by Hofstee plots, increased in the erythrocytes of hypertensive and diabetic patients compared with control cells. In contrast, sulphate influx in the erythrocytes of diabetic and hypertensive patients in the presence of Nifedipine, a calcium antagonist, showed no difference either in the rate constants or in the kinetic profiles, compared to the normotensive control subjects.     

Dietary vitamin C supplementation decreases blood pressure in DOCA-salt hypertensive male Sprague Dawley rats and this is associated with increased liver oxidative stress

The effects of a vitamin C supplemented diet on blood pressure, body and liver weights, liver antioxidant status, iron and copper levels were investigated in DOCA-salt treated and untreated Sprague-Dawley (SD) male rats after 8 weeks of treatment. Vitamin C supplementation had no effect on blood pressure in SD rats but induced a significant decrease in blood pressure in DOCA-salt treated rats, the decrease being more efficient at 50 mg/kg of vitamin C than at 500 mg/kg. Hepatic lipid peroxidation and iron levels were significantly increased in DOCA-salt hypertensive rats whereas total hepatic antioxidant capacity (HAC), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were decreased. Vitamin C supplementation did not affect the overall antioxidant defences of control SD rat livers. In contrast, vitamin C supplementation accentuated the DOCA-salt induced accumulation of liver iron and lipid peroxidation. This occurred without any notable aggravation in the antioxidant deficiency of vitamin C supplemented DOCA-salt treated rat livers. Our data suggest that DOCA-salt treatment induces an accumulation of iron in rat livers which is responsible for the prooxidant effect of vitamin C. The normalization of blood pressure in DOCA-salt treated rats by vitamin C supplementation appears thus independent from liver antioxidant status.     

The role of heme oxygenase signaling in various disorders

Modern methods of cell and molecular biology, augmented by molecular technology, have great potential for helping to unravel the complex mechanisms of various diseases. They also have the potential to help us try to dissect the events which follow the altered physiological conditions. Thus, there is every reason to believe that some of the potential mechanisms will be translated sooner or later into the clinic. Heme oxygenase (HO)-related mechanisms play an important role in several aspects of different diseases. In the past several years, significant progress has been made in our understanding of the function and regulation of HO. The objective of this article is to review current knowledge relating to the importance of HO mechanism in various diseases including myocardial ischemia/reperfusion, hypertension, cardiomyopathy, organ transplantation, endotoxemia, lung diseases, and immunosuppression. The morbidity and mortality of these diseases remain high even with optimal medical management. Furthermore, in this review, we consider various factors influencing the HO system and finally assess current pharmacological approaches to their control.     

Fatty acid composition of brain hemispheres of spontaneously hypertensive rats suckled by female Wistar rats

Total lipid fatty acid composition was investigated in brain hemispheres of male Spontaneously Hypertensive Rats (SHR), compared with normotensive Wistar Kyoto rats (WKY) used as controls. Both strains were suckled by adoptive Wistar mothers, and then fed a standard diet after weaning. No difference was observed between the two hemispheres of WKY killed either at 10 or 30 days. In SHR killed at 10 days, the two hemispheres showed differences, SHR left hemispheres exhibiting greater fatty acid composition changes than those of WKY, phenomenon that toned down at 30 days. Hence, SHR pups showed a different total lipid fatty acid composition of their brain hemispheres when compared with their WKY controls, though the two strains received the same diet. Genetically programmed hypertension might be, directly or not, involved in these changes.     

Increased salt sensitivity secondary to leptin resistance in SHHF rats is mediated by endothelin

A link between leptin resistance, obesity, and salt sensitivity has been suggested. SHHF/Mcc-fa ^cp rats (SHHF) were used to study the effect of gene dosage of a null mutation of the leptin receptor (cp) on salt sensitivity and response to a combined endothelin A and B receptor antagonist (bosentan). Obese (cp/cp), heterozygous (+/cp), and homozygous lean (+/+) male SHHF were fed a low salt diet (0.3% NaCl) for 7 days, followed by a high salt diet (8.0% NaCl) for 7 days. There were no significant differences in systolic blood pressure between genotypes on low salt. In response to high salt, cp/cp had significantly greater systolic pressure than +/cp and +/+. On high salt diet, cp/cp showed a significant increase in 24 h urinary endothelin excretion and increased renal expression of preproendothelin mRNA. There was no effect of high salt diet on renal excretion of nitric oxide (NOx) or on gene expression of endothelial, neuronal, or cytokine-induced nitric oxide synthase isoforms (eNOS, nNOS, iNOS, respectively). Treatment with bosentan prevented the high salt-induced increment in systolic blood pressure in cp/cp. This was associated with a doubling of renal NOx excretion, but without changes in eNOS, nNOS, or iNOS expression. Endothelin receptor antagonism did not normalize systolic pressure in any of the genotypes. Our studies indicate that obesity secondary to leptin resistance (cp/cp) results in increased salt sensitivity that is mediated by endothelin in the SHHF rat.     

Salt-induced hypertension in WKY rats: Prevention by α-lipoic acid supplementation

There is strong evidence that points to excess dietary salt as a major factor contributing to the development of hypertension. Salt sensitivity is associated with glucose intolerance and insulin resistance in both animal models and humans. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes which bind to vascular calcium channels, increasing cytosolic [Ca²⁺]_i and blood pressure. In an insulin resistant animal model of hypertension, spontaneously hypertensive rats (SHRs), dietary supplementation with lipoic acid lowers tissue aldehydes and plasma insulin levels and normalizes blood pressure. The objective of this study is to examine the effects of a high salt diet on tissue aldehydes, cytosolic [Ca²⁺]_i and blood pressure in WKY rats and to investigate whether dietary supplementation with lipoic acid can prevent a salt induced increase in blood pressure. Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each and treated for 10 weeks with diets as follows: WKY-normal salt (0.7% NaCl); WKY-high salt (8% NaCl); WKY-high salt + lipoic acid (8% NaCl diet + lipoic acid 500 mg/Kg feed). At completion, animals in the high salt group had elevated systolic blood pressure, platelet [Ca²⁺]_i, and tissue aldehyde conjugates compared with the normal salt group and showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary -lipoic acid supplementation in high salt-treated WKY rats normalized systolic blood pressure and cytosolic [Ca²⁺]_i and aldehydes in liver and aorta. Kidney aldehydes and renal vascular changes were attenuated, but not normalized.     

Control of cardiomyocyte gene expression as drug target

Pressure overload of the heart is associated with a perturbed gene expression of the cardiomyocyte leading to an impaired pump function. The ensuing neuro-endocrine activation results in disordered influences of angiotensin II and catecholamines on gene expression. To assess whether angiotensin II type 1 receptor inhibition can also counteract a raised sympathetic nervous system activity, spontaneously hypertensive rats fed a hypercaloric diet were treated with eprosartan (daily 90 mg/kg body wt) and cardiovascular parameters were monitored with implanted radiotelemetry pressure transducers. Both, blood pressure and heart rate were increased (p < 0.05) by the hypercaloric diet. Although eprosartan reduced (p < 0.05) the raised systolic and diastolic blood pressure, the diet-induced rise in heart rate was blunted only partially. In addition to drugs interfering with the enhanced catecholamine influence, compounds should be considered that selectively affect cardiomyocyte gene expression via 'metabolic' signals.